Two posters presented at ATS 2025 offered data on Rein Therapeutics’ novel peptide LTI-03’s potential clinical value for idiopathic pulmonary fibrosis patients.


RT’s Three Key Takeaways:

  1. Dual Mechanism of Action: LTI-03 demonstrated both inhibition of profibrotic signaling and promotion of alveolar epithelial cell survival, suggesting a multifaceted therapeutic approach for idiopathic pulmonary fibrosis (IPF).
  2. Superior Safety and Efficacy: In ex vivo and organoid models, LTI-03 effectively reduced profibrotic markers and promoted regeneration without causing cellular necrosis, unlike the current standard treatment, nintedanib.
  3. Regenerative Potential: LTI-03 and its next-generation analog LTI-2355 supported the growth and viability of type 2 alveolar epithelial cells in IPF and normal lungs, indicating potential to restore lung architecture and function in IPF patients.


Rein Therapeutics and its collaborators presented two posters supporting the potential therapeutic effectiveness of LTI-03 in idiopathic pulmonary fibrosis (IPF) at ATS 2025.

“The presentations delivered at ATS today provide further support for the dual mechanism of our lead asset, LTI-03, which has demonstrated sustained alveolar epithelial cell survival as well as inhibition of profibrotic signaling,” said Cory Hogaboam, Ph.D., Chief Scientific Officer of Rein Therapeutics and Professor of Medicine in the Women’s Guild Lung Institute at Cedars Sinai Medical Center.

“Our first presentation highlighted LTI-03’s potent modulatory effects on profibrotic proteins and transcripts as well as its ability to dose-dependently increase the production of soluble receptor of advanced glycation end-products, or solRAGE, without inducing cellular necrosis,” Hogaboam explained.

“Our second presentation used alveolar organoid systems derived from donor or IPF lung epithelial cells to demonstrate LTI-03’s potential to promote and sustain type 2 alveolar epithelial cell, or AEC2, viability in the IPF lung as well as its ability to support AEC2 to type 1 alveolar epithelial cell, or AEC1, differentiation. We continue to be encouraged by the body of evidence supporting the potential of LTI-03 to treat IPF, for which novel treatment options are needed. These findings are in line with the promising data that we reported from the Phase 1b trial of LTI-03 in IPF, and we look forward to sharing topline interim data from our recently initiated Phase 2 RENEW IPF trial in the first half of next year,” said Hogaboam.

First Study

The first poster, entitled, “Pre-clinical Proof-of-concept of Anti-fibrotic Activity of Caveolin-1 Scaffolding Domain Peptide LTI-03 in Ex Vivo Precision Cut Lung Slices (PCLS) from Patients with Idiopathic Pulmonary Fibrosis,” evaluates the antifibrotic effects of LTI-03, Rein’s novel, multi-pathway, Caveolin-1 (Cav1)-related peptide currently in a Phase 2 trial for the treatment of IPF, and of nintedanib, a current standard of care treatment for IPF, in PCLS from 12 patients with end-stage disease. The PCLS samples were treated every 12 hours with one of 0.5 μM, 3.0 μM or 10.0 μM of LTI-03; 0.1 μM or 10.0 μM of nintedanib; or 10.0 μM of placebo, for five to seven days.

Key Takeaways

  • LTI-03 broadly attenuated profibrotic transcripts and proteins and the corresponding pathways of these factors, further supporting LTI-03’s ability to inhibit profibrotic signaling.
  • LTI-03 dose-dependently stimulated production of solRAGE, a factor indicative of AEC1 health that is a critically important aspect of IPF and has gone largely unaddressed by current treatment options.
  • LTI-03 reduced the expression of profibrotic proteins in IPF PCLS, including Col-1α1 and platelet-derived growth factor receptor beta (PDGFRB).
  • Unlike nintedanib, LTI-03 did not induce cellular necrosis or apoptosis.

Second Study

The second poster, entitled, “Evaluating Alveolar Regenerative Properties of Caveolin Scaffolding Peptides (CSD) in Three Dimensional (3D) Alveolospheres from IPF and Normal Donor Lung Samples,” further explores the effects of LTI-03 and nintedanib on AEC2s in the normal and IPF lung. In these studies, the effects of LTI-2355, Rein’s second generation Cav1-related peptide that is in preclinical development, were also examined.

Eight (8) IPF lung explants and 10 normal donor lungs were processed to obtain lung epithelial cell preparations, from which AEC2s were isolated for lung organoid generation. Previous studies completed by Rein and others indicate that there is a significant decrease in the abundance of AEC2s in the IPF lung as compared to a normal lung, in turn impairing AEC2 to AEC1 differentiation and alveolar regeneration. The AEC2s from IPF and normal lung organoids were treated with 0.5 μM, 3.0 μM or 10.0 μM of either LTI-03, LTI-2355 or placebo, or 80.0 nM of nintedanib. Treatments were refreshed every other day in these lung organoid cultures for up to 28 days.

Key Takeaways

  • Cav1 scaffolding domain peptides LTI-03 or LTI-2355 sustained AEC2s in IPF lung organoids or alveolospheres, further supporting LTI-03’s ability to promote alveolar epithelial cell survival.
  • At the 10.0 μM dose, both LTI-03 and LTI-2355 increased the size of IPF alveolospheres compared to placebo at Day 28.
  • Both LTI-03 and LTI-2355 appeared to protect normal lung alveolopheres, while nintedanib demonstrated significant growth-inhibiting or toxic effects on normal donor lung organoids at Day 28.


References

  1. Pergolizzi, Jr., J., LeQuang, J., Varrassi, M., Breve, F., Magnusson, P., Varrassi, G., (2023). What Do We Need to Know About Rising Rates of Idiopathic Pulmonary Fibrosis? A Narrative Review and Update. Springer Nature, Published online 2023 Jan 24. Doi: 10.1007/s12325-022-02395-9.
  2. 2Nathan et al. “Long-term Course and Prognosis of Idiopathic Pulmonary Fibrosis in the New Millennium”. Chest Journal Volume 140, ISSUE 1, P221-229, July 2011.